Botulinum Toxin: An Update on Pharmacology and Newer Products in Development

Abstract

Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic.

Keywords: acetylcholine; botulinum toxin; dystonia; neuromuscular blockade; recombinant botulinum toxin.

Figure 1

Schematic diagram and crystal structure of botulinum toxin type A. X-ray crystallography (PDB ID: 3BTA) shows the molecular organisation of botulinum toxin type A. The schematic representation shows that botulinum toxin type A has two peptide chains connected by a disulphide bridge. The heavy chain has two domains named after their specific activity (binding and translocation). The light chain is responsible for catalytic breakdown of the target protein. KDa = Kilo Dalton: S–S = disulphide bridge, HN = N terminal of heavy chain, HC = C terminal of heavy chain.

Figure 2

Molecular mechanism of botulinum toxin. (A–H) depict representative sequences of events within a synaptic terminal at the neuromuscular junction. (A) The heavy chain of botulinum toxin binds with the surface receptor; (B) The internalisation of the botulinum toxin is possible through its interaction with Sv2 or Syt; (C) Protons enter the synaptic vesicle through an active transporter; (D) The low pH inside the vesicle helps import Ach from the cytoplasm; (E) The translocation domain of botulinum toxin helps in the extrusion of botulinum toxin from the vesicle; (F) The catalytic enzymes act on the botulinum toxin; (G) The light chain is freed from the rest of the toxin; (H) The free and active light chain inactivates the target SNAP receptor (SNARE) proteins (SNAP25, Stx, VAMP). PSG = Polysialoganglioside. HC = Heavy chain, Syt = synaptotagmin, Sv2 = Synaptic vesicle protein 2, Ach = Acetylcholine, LC = light chain, Hsp90 = Heat shock protein 90, TrxR-Trx = Thioredoxin reductase–thioredoxin system, SNAP = soluble NSF attachment protein, NSF = N-ethylmaleimide sensitive fusion protein, SNAP 25 = Synaptosomal-Associated Protein, 25kDa, Stx = Syntaxin, VAMP = Vesicle-associated membrane protein.